Although HIV has been identified as the etiologic agent of AIDS, the mechanisms involved in the conversion of asymptomatic latent HIV infection to overt AIDS are not yet fully elucidated. Heterologous viruses, such as herpes simplex virus (HSV), have been targeted as potential cofactors in the pathogenesis of AIDS. The overall goal of this proposal is to determine how HSV enhances HIV replication and whether HIV, in a bidirectional manner, can modify the expression of HSV. Specifically the aims are: (1) To determine whether HSV and its immediate-early proteins (ICPO, ICP4, and ICP27) can induce HIV replication within normal human mononuclear cells. This will be pursued by establishing acute whole virus coinfection in purified human CD4+ lymphocytes and monocytes with HIV and HSV strains including wild type KOS and isogenic deletion strains. Cultures will be monitored for expression of both HIV and HSV. HIV-1 strains with different cell tropisms and HIV-2 will also be examined. (2) To further define the role of ICP4 in HIV replication and activation. This will be pursued by transfecting ICP4 into both CEM (lymphoid) and U937 (monocytic) cells, followed by superinfection with whole virus HIV-1 and observing for any upregulation in HIV expression. Cotransfection assays utilizing the DEAE-dextran technique will then be performed in CD4+ cell lines and normal human cells to define the potential interaction of ICP4 with the HIV-LTR. (3) To determine whether HSV and selective immediate- early proteins of HSV can induce the activation of latent HIV. This will be studied by superinfecting ACH-2 (lymphoid) and U1 (monocytic) cell lines with wild type KOS strain of HSV or deletion strains and observing for upregulation of HIV expression. Transfection of selected HSV immediate- early proteins into ACH-2 and U1 cells will then be performed to define which HSV proteins are capable of activating latent HIV. (4) To define the ability of HIV to activate latent HSV. This will be pursued by transfection of HSV promoters of immediate-early and early genes linked to CAT constructs, followed by whole virus HIV-1 or HSV superinfection in CEM or U937 cells. HIV will be compared to HSV for its ability to activate the HSV promoter CAT constructs. These studies should more clearly define the mechanisms by which HSV upregulates HIV expression and may indicate whether HSV may serve as a permissive cofactor for HIV replication under certain conditions.